The present invention relates to an improved process for preparing aromatic ring-fused cyclopentane derivatives. Preferably, the present invention relates to an improved process for preparing indane carboxylates and cyclopentanopyridine derivatives. Advantageously, the present invention relates to an improved process for preparing (+) (1S, 2R, 3S)-3-[2-(2-hydroxyeth-1-yloxy)-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid and pharmaceutically acceptable salts thereof and (+) (1S, 2R, 3S)-3-(2-carboxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid and pharmaceutically acceptable salts thereof. Such compounds are described in International Application Number: PCT/US94/04603-International Publication Number WO 94/25013 published on Nov. 10, 1994 and in U.S. Pat. No. 5,389,620, as being useful as endothelin receptor antagonists. Also invented are novel intermediates useful in preparing these compounds.
Processes for the preparation of indane carboxylates, specifically (+) (1S, 2R, 3S)-3-[2-(2-hydroxyeth-1-yloxy)-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid and (+) (1S, 2R, 3S)-3-(2-carboxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid have previously been described. In particular a multistep process to prepare (+) (1S, 2R, 3S)-3-(2carboxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid in 6% overall yield (not including a racemic separation step) from methyl 3-(prop-1-yloxy)benzoylacetate and a multistep process to prepare (+) (1S, 2R, 3S)-3-[2-(2-hydroxyeth-1-yloxy)-4-methoxyphenyl]-1-(3,4 -methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid in 2% overall yield (not including a racemic separation step) from methyl 3-(prop-1-yloxy)benzoylacetate is reported in International Publication Number WO 4/25013, published Nov. 10, 1994. The syntheses of these molecules are complicated by the presence of three chiral centers in each compound.
Processes for the preparation of cyclopentanopyridine derivatives have previously been described. In particular, multistep processes to prepare cyclopentanopyridine derivatives, in low over all yield, are reported in U.S. Pat. No. 5,389,620.
Thus, there is a need in the art for an economical method to prepare indane carboxylates and cyclopentanopyridine derivatives, specifically (+) (1S, 2R, 3S)-3-[2-(2-hydroxyeth-1-yloxy)-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid and pharmaceutically acceptable salts thereof and (+) (1S, 2R, 3S)-3-(2-carboxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid and pharmaceutically acceptable salts thereof.
The numerous advantages of the presently invented process and intermediates will become apparent upon review of the following description.
This invention relates to an improved process for preparing aromatic ring-fused cyclopentane derivatives.
This invention also relates to novel intermediates useful in preparing aromatic ring-fused cyclopentane derivatives.
This invention relates to an improved process for preparing indane carboxylates.
This invention also relates to novel intermediates useful in preparing indane carboxylates.
This invention relates to an improved process for preparing cyclopentanopyridine derivatives.
This invention also relates to novel intermediates useful in preparing cyclopentanopyridine derivatives.
This invention relates to an improved process for preparing (+) (1S, 2R, 3S)-3-(2-(2-hydroxyeth-1-yloxy)-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid and pharmaceutically acceptable salts thereof, preferably the ethylene diamine 2:1 salt.
This invention relates to novel intermediates useful in preparing (+) (1S, 2R, 3S)-3-[2-(2-hydroxyeth-1-yloxy)-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl) -5-(prop-1-yloxy)indane-2-carboxylic acid.
This invention relates to an improved process for preparing (+) (1S, 2R, 3S)-3-(2-carboxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid and pharmaceutically acceptable salts thereof, preferably the disodium salt.
This invention relates to novel intermediates useful in preparing (+) (1S, 2R, 3S)-3-(2-carboxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid.
Unless otherwise defined, the term xe2x80x98aromatic ring-fused cyclopentane derivativesxe2x80x99 as used herein, is meant the racemic compounds of Formula (1): 
wherein A, B, C and D are carbon atoms or three of A, B, C and D are carbon atoms and one is a nitrogen atom;
R1 is 
where R3 and R4 are independently H, OH, protected OH, C1-8alkoxy, I, Br, Cl, F, CF3 or C1-6alkyl and R5 is xe2x80x94OCH2CO2H or xe2x80x94OCH2CH2OH;
R2 is 
where R3 and R4 are as indicated above and
Z is H, OH, or C1-5alkoxy;
or a pharmaceutically acceptable salt thereof.
Preferred among the racemic compounds of Formula (1) are the compounds of Formula (17): 
wherein A, B, C, D, R1, R2 and Z are as described in Formula (1);
or a pharmaceutically acceptable salt thereof.
By the term indane carboxylates as used herein is meant the racemic compounds of: Formula (2): 
wherein R1, R2 and Z are as described in Formula (1);
or a pharmaceutically acceptable salt thereof.
Preferred among the racemic compounds of Formula (2) are the compounds of Formula (18): 
wherein R1, R2 and Z are as described in Formula (1); or a pharmaceutically acceptable salt thereof.
By the term cyclopentanopyridine derivatives as used herein is meant the racemic compounds of Formula (3): 
wherein three of A, B, C and D are carbon atoms and one is a nitrogen atom; and R1, R2 and Z are as described in Formula (1);
or a pharmaceutically acceptable salt thereof.
Preferred among the racemic compounds of Formula (3) are the compounds of Formula (19): 
wherein three of A, B, C and D are carbon atoms and one is a nitrogen atom; and
R1, R2 and Z are as described in Formula (1);
or a pharmaceutically acceptable salt thereof.
In Formula (3) compounds, in Formula (19) compounds and in Formula (1) compounds when one of A, B, C or D is a nitrogen atom, preferably A is nitrogen.
Pharmaceutically acceptable salts of the compounds of Formulas (1), (2), (3), (17), (18) and (19) are formed where appropriate by methods well known to those of skill in the art.
Pharmaceutically acceptable salts of (+) (1S, 2R, 3S)-3-[2-2-hydroxyeth-1-yloxy)-4methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid and (+) (1S, 2R, 3S)-3-(2-carboxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2carboxylic acid are formed where appropriate by methods well known to those of skill in the art.
By the term xe2x80x9cPrxe2x80x9d as used herein is meant n-propyl.
The term xe2x80x98activation reactionxe2x80x99 for use herein refers to the numerous reactions and reaction conditions well known to those skilled in the art to effect the introduction of a Br, I, xe2x80x94OSO2CF3 or a xe2x80x94OSO2F substituent.
By the term xe2x80x98chiral reductionxe2x80x99 as used herein refers to reagents and reaction conditions that effect an enantioselective reduction, preferably using, a chiral catalyst, most preferably using (R)-3,3-diphenyl-1-methyltetrahydro-1H, 3H-pyrrolo-[1,2-c][1.3.2]oxazaborole (as used hereinafter and in the claims (R)-MeCBS which is available from the Callery Chemical Co. of Evans City, Pa.).
The term (+) (1S, 2R, 3S)-3-[2-(2-hydroxyeth-1-yloxy)-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid as used herein utilizes standard chemical terminology and refers to compound (o) 
The term (+) (1S, 2R, 3S)-3-[2-(2-hydroxyeth-1-yloxy)-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid ethylene diamine salt (2:1) as used herein utilizes standard chemical terminology and refers to Compound (p) 
The term (+) (1S, 2R, 3S)-3-(2-carboxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid as used herein utilizes standard chemical terminology and refers to compound (k) 
The term (+) (1S, 2R, 3S)-3-(2-carboxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid disodium salt as used herein utilizes standard chemical terminology and refers to Compound (1) 
The indane carboxylates of Formula (18) of the current invention are prepared by methods outlined in the Schemes below and in the Examples from compounds of Formula (a): 
where R is H, OH, C1-5alkoxy (preferably n-PrO) or a protected oxy group, such as benzyloxy. Compounds of Formula (a) are known or can be prepared from readily available starting materials by those skilled in the art.
By the term xe2x80x98oxy protecting groupxe2x80x99, xe2x80x98protected oxy groupxe2x80x99 and xe2x80x98protected OHxe2x80x99 as used herein, is meant any conventional blocking group in the art such as described in xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d by Theodora W. Greene, Wiley-Interscience, 1981, New York, provided that such oxy protecting group, protected oxy group or such protected OH do not include moieties that render inoperative the presently invented process. A preferred oxy protecting group for use herein is benzyl. A preferred protected OH or protected oxy group for use herein is benzyloxy. When necessary or desired, the deprotection of the protected oxy or the protected OH is performed on products of the synthetic pathways disclosed or claimed herein or, where appropriate or preferable on certain intermediates in these synthetic pathways.
Further, when necessary or desired, R can be converted to a substituent of Z. Reactions to convert R to Z are performed on products of the synthetic pathways disclosed or claimed herein or, where appropriate or preferable on certain intermediates in the synthetic pathways. For example, hydroxyl groups can be converted into C1-5alkoxy groups by alkylation. Protected oxy groups can be deprotected and further reacted to form a substituent of Z.
The present invention provides an improved process for the production of indane carboxylates of Formula (18) as indicated in Schemes 1 and 2 below. 
Scheme 1 outlines formation of indane carboxylates wherein R5 is xe2x80x94OCH2CO2H, preferably the disodium salt, Compound (1). As used in Scheme 1, R3 and R4 are as described in Formula (1), R is as described in Formula (a), R7 is Br, 1, xe2x80x94OSO2CF,3 or xe2x80x94OSO2F, and R8 is Br, I, xe2x80x94OSO2CF3 or xe2x80x94OSO2F and R9 is an oxy protecting group. Compounds of Formula (b) are prepared in one or more steps by treating a compound of Formula (a) in an activation reaction, preferably with hexamethylenetetramine hydrobromide perbromide, to introduce substituent R7. Compounds of Formula (c) are prepared by treating the compounds of Formula (b) with an appropriately substituted piperonal and sodium methoxide. Compounds of Formula (d) are prepared by treating Formula (c) compounds with a phosphine, preferably triphenylphosphine, a base, preferably potassium carbonate and a palladium catalysts, preferably palladium(II) chloride. Compounds of Formula (d) are treated in a chiral reduction, preferably with a chiral catalyst, most preferably with (R)-3,3-diphenyl-1-methyltetrahydro-1H, 3H-pyrrolo-[1, 2-c][1.3.2]oxazaborole (as used hereinafter and in the claims (R)-MeCBS which is available from the Callery Chemical Co. of Evans City, Pa.), a borane complex, preferably borane-tetrahydrofuran complex, and a base, preferably triethylamine, to give compounds of Formula (e) as the predominately pure enantiomer. Treatment of Formula (e) compounds with a base, such as triethylamine, and a palladium catalyst, such as [1,2-bis(diphenylphosphino)ethane] palladium (H) chloride (as used hereinafter and in the claims Pd(dppe)Cl2 which is available from the Strem
Chemical Co. of Newburyport Ma.) gives compounds of Formula (f) as the predominately pure enantiomer. Treatment of Formula (f) compounds with dimethyl carbonate, sodium hydride and sodium methoxide gives compounds of Formula (g). Compounds of Formula (h) are prepared by treating Formula (g) compounds in an activation reaction, preferably with sodium hydride and fluorosulfonic anhydride, to introduce substituent R8. Compounds of Formula (i) are prepared by the catalytic coupling of Formula (h) compounds and Formula (u) compounds, preferably using [1,1xe2x80x2-bis(diphenylphosphino)ferrocene] palladium (II) chloride (as used hereinafter and in the claims Pd(dppf)Cl2 which can be purchased from the Strem Chemical Co. of Newburyport, Mass.). Hydrogenation of Formula (i) compounds with a palladium catalyst, preferably palladium hydroxide on carbon, gives compounds of Formula (j). Compounds of Formula (6), preferably Compound (k) as used herein, are prepared by treating Formula (j) compounds with methyl bromoacetate, a base, preferably potassium carbonate, followed by treatment with lithium hydroxide monohydrate or sodium hydroxide and acid workup. Compounds of Formula (6) are treated with sodium hydroxide to give Formula (7) compounds, preferably Compound (1) as used herein. 
Scheme 2 outlines formation of indane carboxylates wherein R5 is xe2x80x94OCH2CH2OH, preferably the ethylene diamine salt (2:1), Compound (p). As used in Scheme 2, R3 and R4 are as described in Formula (1), R is as described in Formula (a), R7 is Br, I, xe2x80x94OSO2CF3 or xe2x80x94OSO2F, R8 is Br, I, xe2x80x94OSO2CF3 or xe2x80x94OSO2F and R9 is an oxy protecting group. As used in Scheme 2 a compound of Formula (h) from Scheme 1 is coupled with a compound of Formula (v) using a catalyst, preferably Pd(dppf)Cl2 to give compounds of Formula (m). Hydrogenation of Formula (m) compounds with a palladium catalyst, preferably palladium hydroxide on carbon gives compounds of Formula (n). Compounds of Formula (8), preferably Compound (o) as used herein, are prepared by treating Formula (n) compounds with lithium hydroxide monohydrate. Compounds of Formula (8) are treated with ethylene diamine to give Formula (9) compounds, preferably Compound (p) as used herein.
The racemic compounds of Formulas (1), (2) and (3) are prepared according to the methods outlined in Schemes (1) and (2) and in the Examples by substituting a compound of Formula (10): 
wherein A, B, C and D are carbon atoms or three of A, B, C and D are carbon atoms and one is a nitrogen atom and R is H, OH, C1-5alkoxy (preferably n-PrO) or a protected oxy group, such as benzyloxy, for the compound of Formula (a) and by substituting an achiral reduction, such as using sodium borohydride in methanol, for the chiral reduction used to convert compounds of Formula (d) to compounds of Formula (e) in Scheme 1.
Compounds of Formula (10) are known or can be prepared from readily available starting materials by those skilled in the art.
Thus, an achiral reduction is substituted for the chiral reduction used to convert compounds of Formula (d) to compounds of Formula (e) in Scheme 1 to prepare compounds of Formula (2) and intermediates useful in preparing compounds of Formula (2). The compounds of Formula (10) are utilized in Scheme 1, by substituting an achiral reduction for the chiral reduction used to convert compounds of Formula (d) to compounds of Formula (e) in Scheme 1, to prepare compounds of Formula (1) and intermediates useful in preparing compounds of Formula (1). The compounds of Formula (10), wherein three of A, B, C and D are carbon atoms and one is a nitrogen atom, are utilized in Scheme 1, by substituting an achiral reduction for the chiral reduction used to convert compounds of Formula (d) to compounds of Formula (e) in Scheme 1, to prepare compounds of Formula (3) and intermediates useful in preparing compounds of formula (3).
The cyclopentano[b]pyridine derivatives of Formula (19) of the current invention are prepared according the methods outlined in Schemes 1 and 2 and in the Examples from compounds of Formula (10) wherein three of A, B, C and D are
carbon atoms and one is a nitrogen atom. Preferred among Formula (10) compounds when a nitrogen is present are those wherein A is nitrogen.
The aromatic ring-fused cyclopentane derivatives of Formula (17) of the current invention are prepared according the methods outlined in Schemes 1 and 2 and in the Examples from compounds of Formula (10) wherein A, B, C and D are carbon atoms or three of A, B, C and D are carbon atoms and one is a nitrogen atom. Preferred among Formula (10) compounds when a nitrogen is present are those wherein A is nitrogen.
Prepared in synthesizing the indane carboxylates of Formula (18), preferably Compound (1) and Compound (p), are novel intermediates of Formula (b): 
where R is as described in Formula (a) and R7 is Br, I, xe2x80x94OSO2CF3 or xe2x80x94OSO2F.
Also prepared in synthesizing the indane carboxylates of Formula (18), preferably Compound (1) and Compound (p), are novel intermediates of Formula (c): 
where R3and R4 as described in Formula (1), R is as described in Formula (a), and R7 is Br, I, xe2x80x94OSO2CF3 or xe2x80x94OSO2F.
Also prepared in synthesizing the indane carboxylates of Formula (18), preferably Compound (1) and Compound (p), are novel intermediates of Formula (d): 
where R3 and R4 are as described in Formula (1) and R is as described in Formula (a).
Also prepared in synthesizing the indane carboxylates of Formula (18), preferably Compound (1) and Compound (p), are novel intermediates of Formula (e): 
where R3 and R4 are as described in Formula (1) and R is as described in Formula (a).
Also prepared in synthesizing the indane carboxylates of Formula (18), preferably Compound (1) and Compound (p), are novel intermediates of Formula (f): 
where R3 and R4 are as described in Formula (1) and R is as described in Formula (a).
Also prepared in synthesizing the indane carboxylates of Formula (18), preferably Compound (1) and Compound (p), are novel intermediates of Formula (g): 
where R3 and R4 are as described in Formula (1) and R is as described in Formula (a).
Also prepared in synthesizing the indane carboxylates of Formula (18), preferably Compound (1) and Compound (p), are novel intermediates of Formula (h): 
where R3 and R4 are as described in Formula (1), R is as described in Formula (a) and R8 is Br, I, xe2x80x94OSO2CF3 or xe2x80x94OSO2F.
Also prepared in synthesizing the indane carboxylates of Formula (18), preferably Compound (1), are novel intermediates of Formula (i): 
where R3 and R4 are as described in Formula (1), R is as described in Formula (a) and R9 is an oxy protecting group.
Also prepared in synthesizing the indane carboxylates of Formula (18), preferably Compound (1), are novel intermediates of Formula (j): 
where R3 and R4 are as described in Formula (1) and R is as described in Formula (a).
Also prepared in synthesizing the indane carboxylates of Formula (18), preferably Compound (p), are novel intermediates of Formula (m): 
where R3 and R4 are as described in Formula (1), R is as described in Formula (a) and R9 is an oxy protecting group.
Also prepared in synthesizing the indane carboxylates of Formula (18), preferably Compound (p), are novel intermediates of Formula (n): 
where R3 and R4 are as described in Formula (1) and R is as described in Formula (a).
Prepared in synthesizing the aromatic ring-fused cyclopentane derivatives of Formula (1) are novel intermediates of Formula (10): 
wherein A, B, C and D are carbon atoms or three of A, B, C and D are carbon atoms and one is a nitrogen atom and R is as described in Formula (a).
Prepared in synthesizing the cyclopentanopyridine derivatives of Formula (19) are intermediates of Formula (10) where three of A, B, C and D are carbon atoms and one is a nitrogen atom and R is as described in Formula (a).
Also prepared in synthesizing the aromatic ring-fused cyclopentane derivatives of Formula (1) are novel intermediates of Formula (11): 
wherein A, B, C and D are carbon atoms or three of A, B, C and D are carbon atoms and one is a nitrogen atom, R is as described in Formula (a) and R7 is Br, I, xe2x80x94OSO2CF3 or xe2x80x94OSO2F.
Also prepared in synthesizing the cyclopentanopyridine derivatives of Formula (19) are intermediates of Formula (11) where three of A, B, C and D are carbon atoms and one is a nitrogen atom, R is as described in Formula (a) and R7 is Br, I, xe2x80x94OSO2CF3 or xe2x80x94OSO2F.
Also prepared in synthesizing the aromatic ring-fused cyclopentane derivatives of Formula (1) are novel intermediates of Formula (12): 
wherein A, B, C and D are carbon atoms or three of A, B, C and D are carbon atoms and one is a nitrogen atom, R is as described in Formula (a) and R7 is Br, I, xe2x80x94OSO2CF3 or xe2x80x94OSO2F.
Also prepared in synthesizing the cyclopentanopyridine derivatives of Formula (19) are intermediates of Formula (12) where three of A, B, C and D are carbon atoms and one is a nitrogen atom, R is as described in Formula (a) and R7 is Br, I, xe2x80x94OSO2CF3 or xe2x80x94OSO2F.
Also prepared in synthesizing the aromatic ring-fused cyclopentane derivatives of Formula (1) are novel intermediates of Formula (13): 
wherein A, B, C and D are carbon atoms or three of A, B, C and D are carbon atoms and one is a nitrogen atom, R is as described in Formula (a) and R7 is Br, I, xe2x80x94OSO2CF3 or xe2x80x94OSO2F.
Also prepared in synthesizing the cyclopentanopyridine derivatives of Formula (19) are intermediates of Formula (13) where three of A, B, C and D are carbon atoms and one is a nitrogen atom, R is as described in Formula (a) and R7 is Br, I, xe2x80x94OSO2CF3 or xe2x80x94OSO2F.
Also prepared in synthesizing the cyclopentanopyridine derivatives of Formula (3) are the novel racemic intermediates of Formula (14): 
wherein three of A, B, C and D are carbon atoms and one is a nitrogen atom, R is as described in Formula (a) and R3 and R4 are as described in Formula (1).
Also prepared in synthesizing the cyclopentanopyridine derivatives of Formula (19) are the novel intermediates of Formula (15): 
wherein three of A, B, C and D are carbon atoms and one is a nitrogen atom, R is as described in Formula (a) and R3 and R4 are as described in Formula (1).
Also prepared in synthesizing the cyclopentanopyridine derivatives of Formula (3) are the novel racemic intermediates of Formula (16): 
wherein three of A, B, C and D are carbon atoms and one is a nitrogen atom, R is as described in Formula (a) and R3 and R4 are as described in Formula (1).
Also prepared in synthesizing the cyclopentanopyridine derivatives of Formula (19) are the novel intermediates of Formula (20): 
wherein three of A, B, C and D are carbon atoms and one is a nitrogen atom, R is as described in Formula (a) and R3 and R4 are as described in Formula (1).
Also prepared in synthesizing the cyclopentanopyridine derivatives of Formula (3) are the novel racemic intermediates of Formula (21): 
wherein three of A, B, C and D are carbon atoms and one is a nitrogen atom, R is as described in Formula (a) and R3 and R4 are as described in Formula (1).
Also prepared in synthesizing the cyclopentanopyridine derivatives of Formula (19) are the novel intermediates of Formula (22): 
wherein three of A, B, C and D are carbon atoms and one is a nitrogen atom, R is as described in Formula (a) and R3 and R4 are as described in Formula (1).
Also prepared in synthesizing the cyclopentanopyridine derivatives of Formula (3) are the novel racemic intermediates of Formula (23): 
wherein three of A, B, C and D are carbon atoms and one is a nitrogen atom, R3 and R4 are as described in Formula (1), R is as described in Formula (a) and R8 is Br, I, xe2x80x94OSO2CF3 or xe2x80x94OSO2F.
Also prepared in synthesizing the cyclopentanopyridine derivatives of Formula (19) are the novel intermediates of Formula (24): 
wherein three of A, B, C and D are carbon atoms and one is a nitrogen atom, R3 and R4 are as described in Formula (1), R is as described in Formula (a) and R8 is Br, I, xe2x80x94OSO2CF3 or xe2x80x94OSO2F.
Also prepared in synthesizing the cyclopentanopyridine derivatives of Formula (3) are the novel racemic intermediates of Formula (25): 
wherein three of A, B, C and D are carbon atoms and one is a nitrogen atom, R is as described in Formula (a), R3 and R4 are as described in Formula (1) and R9 is an oxy protecting group.
Also prepared in synthesizing the cyclopentanopyridine derivatives of Formula (19) are the novel intermediates of Formula (26): 
wherein three of A, B, C and D are carbon atoms and one is a nitrogen atom, R is as described in Formula (a), R3 and R4 are as described in Formula (1) and R9 is an oxy protecting group.
Also prepared in synthesizing the cyclopentanopyridine derivatives of Formula (3) are the novel racemic intermediates of Formula (27): 
wherein three of A, B, C and D are carbon atoms and one is a nitrogen atom, R is as described in Formula (a) and R3 and R4 are as described in Formula (1).
Also prepared in synthesizing the cyclopentanopyridine derivatives of Formula (19) are the novel intermediates of Formula (28): 
wherein three of A, B, C and D are carbon atoms and one is a nitrogen atom, R is as described in Formula (a) and R3 and R4 are as described in Formula (1).
Also prepared in synthesizing the cyclopentanopyridine derivatives of Formula (3) are the novel racemic intermediates of Formula (29): 
wherein three of A, B, C and D are carbon atoms and one is a nitrogen atom, R is as described in Formula (a), R3 and R4 are as described in Formula (1) and R9 is an oxy protecting group.
Also prepared in synthesizing the cyclopentanopyridine derivatives of Formula (19) are the novel intermediates of Formula (30): 
wherein three of A, B, C and D are carbon atoms and one is a nitrogen atom, R is as described in Formula (a), R3 and R4 are as described in Formula (1) and R9 is an oxy protecting group.
Also prepared in synthesizing the cyclopentanopyridine derivatives of Formula (3) are the novel racemic intermediates of Formula (31): 
wherein three of A, B, C and D are carbon atoms and one is a nitrogen atom, R is as described in Formula (a) and R3 and R4 are as described in Formula (1).
Also prepared in synthesizing the cyclopentanopyridine derivatives of Formula (19) are the novel intermediates of Formula (32): 
wherein three of A, B, C and D are carbon atoms and one is a nitrogen atom, R is as described in Formula (a) and R3 and R4 are as described in Formula (1).
All of the starting materials and reagents used herein are known and readily available or can be easily made from known and readily available reagents.
For example, compounds of Formula (u) are prepared according to the following steps:
a) treating a compound of the formula 
where R3 and R4 are as described in Formula (1), in a reaction to convert the OH to a protected oxy group, such as benzyl bromide and sodium hydride in N,N-dimethylformamide, to form the compound 
where R3 and R4 are as described in Formula (1) and R9 is an oxy protecting group,
b) treating the product of step a) with magnesium turnings, 1,2-dibromoethane and trimethylborate (B(OMe)3) in tetrahydrofuran to form compounds of Formula (u) 
where R3 and R4 are as described in Formula (1) and R9 is an oxy protecting group.
For example, compounds of Formula (v) are prepared according to the following steps:
a) treating a compound of the formula 
where R3 and R4 are as described in Formula (1), with benzyloxyethyl bromide or another suitable protected oxy group, a base, such as potassium carbonate, to form compounds of Formula (ab) 
where R3 and R4 are as described in Formula (I) and R9 is an oxy protecting group,
b) treating the product of step a) with magnesium turnings, 1,2-dibromoethane and trimethylborate (B(OMe),) in tetrahydrofuran to form compounds of Formula (v) 
where R3 and R4 are as described in Formula (1) and R9 is an oxy protecting group.